Growing Together: How Viruses Have Shaped Human Evolution. Shirlee Wohl Katherine Wu

Growing Together: How Viruses Have Shaped Human Evolution Shirlee Wohl Katherine Wu

What comes to your mind when you hear the word virus? flu public health cold vaccine infection disease cough biology HIV Ebola bacteria epidemic computer software germ swine flu contagious

Today s lecture 1. A quick introduction to viruses 2. Viruses & the human genome 3. Viruses & our bodies

What is a virus? Virus = a small infectious agent that only replicates inside cells of other organisms

What is a virus? Virus = a small infectious agent that only replicates inside cells of other organisms virus envelope capsi d genetic material (DNA or RNA)

What is a virus? Viruses that infect humans include: Influenza (RNA) Smallpox (DNA) HIV (RNA) Ebola (RNA)

Introduction to viruses human cell: 10x smaller than the width of a human hair Figure by Joy Jiao

Introduction to viruses bacteria: 5x smaller than a human cell human cell: 10x smaller than the width of a human hair Figure by Joy Jiao

Introduction to viruses bacteria: 5x smaller than a human cell virus: 40x smaller than a bacteria! human cell: 10x smaller than the width of a human hair Only 10% of the cells in our body are human Figure by Joy Jiao

Introduction to viruses 10% of our DNA is viral! Figure by Joy Jiao

The central dogma DNA RNA protein

The viral life cycle Influenza (RNA) human cell protein Adapted from figure by Joy Jiao RNA

Questions?

Today s lecture 1. A quick introduction to viruses 2. Viruses & the human genome 3. Viruses & our bodies

Viruses in the human genome Some viruses can insert themselves into the DNA of other organisms (including humans) These viruses are called retroviruses

How do retroviruses get into human DNA? DNA RNA reverse transcriptase Retroviruses can go backwards!

The retrovirus life cycle HIV (RNA) human cell RNA reverse transcriptase DNA protein RNA DNA Adapted from figure by Joy Jiao

Not all retroviruses make us sick Exogenous retroviruses: infectious viruses HIV HIV Endogenous retroviruses: fossil viruses

Why don t endogenous retroviruses make us sick? Mutations during DNA replication We re left with fragments of viral genomes that don t produce actual viruses CTGATAAGAGG CTGATTAGAGG

Summary Viruses than can insert themselves into host DNA are called retroviruses Retroviruses can go backwards and convert RNA to DNA, which can be inserted into host DNA 10% of human DNA is retrovirus fragments that can t make you sick

Questions?

What is gene therapy? mutated gene RPE65 gene Hereditary blindness CTGATAAGAGG CTGAAGTCAGG

What is gene therapy? mutated RPE65 gene retrovirus injection of retrovirus into eye normal gene added to human DNA in eye cells RPE65 protein made normally = vision restored!

What is gene therapy? mutated RPE65 gene retrovirus Wait what? Scientists can do that? normal gene added to human DNA in eye cells RPE65 protein made normally = vision restored!

What is gene therapy? mutated RPE65 gene retrovirus Then why do people still suffer from genetic disorders? normal gene added to human DNA in eye cells RPE65 protein made normally = vision restored!

Common genetic disorders Color blindness Cystic fibrosis Down syndrome Huntington s disease Muscular dystrophy Hemophilia Sickle-cell anemia Many more

Limitations of gene therapy Risks associated with gene therapy: Viruses can infect more than one kind of cell New gene might be inserted in the wrong place Body might not react well to the virus We can only insert small genes

Summary Retroviruses can be really bad (e.g. HIV) Retroviruses can be useful tools for studying human history In gene therapy, retroviruses are used for good Gene therapy has many limitations right now, but is a promising new technique

Questions?

Today s lecture 1. A quick introduction to viruses 2. Viruses & the human genome 3. Viruses & our bodies

VIRUSES & OUR BODIES Katherine Wu

1.Monsters inside me! (not really): the human virome 2.VirScan: probing our viral history

Only 10% of the cells in our body are human Really, we are just luxurious condos for microbes Figures by Joy Jiao

Figures by Joy Jiao Microbiome: the collection of microbes that share our body space

5x 40x Virome: the collection of viruses that share our body space Figures by Joy Jiao

HUMAN BACTERIA L VIRAL

DNA is DNA: when DNA is sequenced, we cannot tell what is what

HUMAN BACTERIA L VIRAL UNKNOWN

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Illumina sequencing machine

QUESTIONS? Wikimedia Commons

The Virome & Host Protection

Healthy mouse Pathogenic bacteria (Citrobacter rodentium) Healthy mouse Our gut microbiome defends us against infection: friendly bacteria usually outcompete foreigners Adapted from Kernbauer et al. 2015

Healthy mouse Antibiotics Pathogenic bacteria (Citrobacter rodentium) If the bacterial microbiome is disrupted by antibiotics or other stressors, most of the population is destroyed and can no longer defend against infection Adapted from Kernbauer et al. 2015

? Healthy mouse Antibiotics Adapted from Kernbauer et al. 2015 Pathogenic bacteria (Citrobacter rodentium)

Healthy mouse Antibiotics Pathogenic bacteria (Citrobacter rodentium) Adapted from Kernbauer et al. 2015 Symbiotic virus (murine norovirus)

Friendly Phage Most gut viruses co-exist symbiotically with their bacterial hosts Bacteriophage: a virus that specifically infects bacteria Wikimedia Commons

Phage & Bacterial Population Dynamics

Consider a population of bacterial cells Figures by Joy Jiao

Consider a population of bacterial cells infected by phage! Figures by Joy Jiao

We re all winners. Figures by Joy Jiao

We re all winners. Except for the losers. Figures by Joy Jiao

Gaining the Upper Hand Enterococcus faecalis encodes phage genes that are only expressed when E. faecalis is in the gut Expression of these genes is associated with E. faecalis outcompeting its neighbors Adapted from Duerkop et al. 2012

Gaining the Upper Hand How can we use this information Enterococcus faecalis encodes phage genes that are only expressed when E. faecalis is in the gut to our advantage? Expression of these genes is associated with E. faecalis outcompeting its neighbors Adapted from Duerkop et al. 2012

Just Add Virus! Phages infect and kill bacteria good and bad There are many kinds of phage, and they recognize only specific bacterial targets Phage therapy: the use of bacteriophages to selectively kill pathogenic bacteria. Figures by Joy Jiao

1919 Felix d Herelle uses phages to treat dysentery in Paris 1915 Bacteriophage first identified 1896 Ernest Hankin finds filtered water contains a substance that can kill Vibrio cholerae 1923 Eliava Institute founded in Georgia to develop phage therapy

1915 Bacteriophage first identified 1919 Felix d Herelle uses phages to treat dysentery in Paris 1941 Discovery of antibiotics 1896 Ernest Hankin finds filtered water contains a substance that can kill Vibrio cholerae 1923 Eliava Institute founded in Georgia to develop phage therapy

1915 Bacteriophage first identified 1919 Felix d Herelle uses phages to treat dysentery in Paris 1941 Discovery of antibiotics the dark years 1896 Ernest Hankin finds filtered water contains a substance that can kill Vibrio cholerae 1923 Eliava Institute founded in Georgia to develop phage therapy

1915 Bacteriophage first identified 1919 Felix d Herelle uses phages to treat dysentery in Paris 1941 Discovery of antibiotics c.1985 onward Rise of antibiotic resistance the dark years 1896 Ernest Hankin finds filtered water contains a substance that can kill Vibrio cholerae 1923 Eliava Institute founded in Georgia to develop phage therapy 2009 First phase I randomized clinical trial performed in the U.S. published

Antibiotics Drug resistance Broad spectrum Multiple side effects Slow, expensive development of new drugs Phage therapy Still effective against drug-resistant strains Specific Cost-effective No side effects

Summary The vast majority of viruses we come into contact with are within our own bodies. Our virome 1) interacts with and stabilizes our microbiome; 2) affects our susceptibility to disease; 3) modulates our metabolism; and much more. We can co-opt these viral functions in the form of phage therapy to treat bacterial disease.

QUESTIONS? Healthy mouse Antibiotics Pathogenic bacteria (Citrobacter rodentium) Symbiotic virus (murine norovirus)

1.Monsters inside me! (not really): the human virome 2.VirScan: probing our viral history

The Viral Archives 10% of our genome is viral (retroviruses!)

Not All Human 10% of our genome is viral But viral information is stored in our bodies in other ways as well Can you remember every infection you ve ever had?

Not All Human 10% of our genome is viral But viral information is stored in our bodies in other ways as well Can you remember every infection you ve ever had? Luckily, our brain isn t the only part of the body that has memory

Antibodies Antibodies bind antigens Pieces of bacteria, viruses, and other pathogens Dust and other allergens Pieces of damaged or dead human cells Wikimedia Commons

Antibodies Antibodies bind antigens Memory B cells respond faster and more effectively to antigen Our antibodies are an archive of infection Wikimedia Commons

I have an infection. hepatitis C antigen hepatitis C antibody Do I have Hepatits C? Positive: Yes, it is Hepatitis C. Negative: No, it is not Hepatitis C.

Profiling the Archives with VirScan Antigens from all 206 species (and over 1000 strains total) of viruses known to infect humans Figures by Joy Jiao, and adapted from Xu et al.

Profiling the Archives with VirScan Figures by Joy Jiao, and adapted from Xu et al.

Profiling the Archives with VirScan Figures by Joy Jiao

Profiling the Archives with VirScan Samples from 569 subjects ~10 viruses per person (up to 84!) Illumina sequencing machine Figures by Joy Jiao

Current tests Single specificity Uninformative negative Fast (days) High accuracy False positives possible VirScan Can detect any virus known to infect humans Fast (days) High accuracy False positives possible Can identify asymptomatic infections

Summary Antibodies are a part of our immunological memory. We now have powerful sequencing and computational tools to take advantage of this memory and interrogate past viral infections. With tests like VirScan, we no longer need to test for infections one pathogen at a time.

What comes to your mind when you hear the word virus? flu public health cold vaccine infection disease cough biology HIV Ebola bacteria epidemic computer software germ swine flu contagious

What comes to your mind when you hear the word virus? evolution public health vaccine antibodies flu symbiosis cold infection phage therapy cough disease gene therapy software computer HIV biology treatment virome Ebola germ swine flu bacteria bacteriophage contagious diagnosis epidemic unexplored

QUESTIONS?

Thank you! SITN would like to acknowledge the following organizations for their generous support. Harvard Medical School Office of Communications and External Relations Division of Medical Sciences The Harvard Graduate School of Arts and Sciences (GSAS) The Harvard Graduate Student Council (GSC) The Harvard/MIT COOP